Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia

Abstract

Objectives: An association between physical inactivity and worse outcome during infectious disease has been reported. The effect of moderate exercise preconditioning on the immune response during an acute pneumonia in a murine model was evaluated.

Setting: Laboratory experiments.

Subjects: C57BL6/j male mice.

Interventions: Six-week-old C57BL/6J mice were divided in two groups: an exercise group and a control group. In the exercise group, a moderate, progressive, and standardized physical exercise was applied for 8 weeks. It consisted in a daily treadmill training lasting 60 minutes and with an intensity of 65% of the maximal theoretical oxygen uptake. Usual housing recommendation were applied in the control group during the same period. After 8 weeks, pneumonia was induced in both groups by intratracheal instillation of a fixed concentration of a Klebsiella pneumoniae (5 × 103 colony-forming unit) solution.

Measurements and main results: Mice preconditioned by physical exercise had a less sever onset of pneumonia as shown by a significant decrease of the Mouse Clinical Assessment Severity Score and had a significantly lower mortality compared with the control group (27% vs. 83%; p = 0.019). In the exercise group, we observed a significantly earlier but transient recruitment of inflammatory immune cells with a significant increase of neutrophils, CD4+ cells and interstitial macrophages counts compared with control group. Lung tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 were significantly decreased at 48 hours after pneumonia induction in the exercise group compared with the control group.

Conclusions: In our model, preconditioning by moderate physical exercise improves outcome by reducing the severity of acute pneumonia with an increased but transient activation of the innate immune response.

Figure 1.

Metabolism and inflammation at basal state. A, Food consumption during 8 wk of exercise (n = 56 mice per group). B, Weight variation during 8 wk of exercise (n = 56 mice per group). C, Heatmap of plasma circulating cytokines after exercise period or sedentary period. (n = 5–6 per group). *p < 0.05. GM-CSF = granulocyte-macrophage colony-stimulating factor, IFNγ = interferon gamma, IL = interleukin, KC/CXCL1 = keratinocyte-derived chemokine (KC) (also known as CXCL1 [chemokine C-X-C motif ligand 1]), LIX = lipopolysaccharide-induced CXC chemokine, MCP-1 = monocyte chemoattractant protein-1, MP-2 = macrophage inflammatory protein-2, TNF-α = tumor necrosis factor alpha.

Figure 2.

The exercise modifies the prognosis associated with sepsis. A, Survival after pneumonia induction (n = 12 sedentary and n = 11 exercise mice). **p < 0.01. B, Mouse Clinical Assessment Severity Score (M-CASS) between sedentary and exercise group (n = 12 or 11 per group). C, Number of colony-forming unit (CFU) per g of lung during pneumonia in sedentary or exercise mice (n = 9 per group at 24 and 48 hr). *p < 0.05. D, Histological analysis using hematoxylin and eosin (HE) of Klebsiella pneumoniae–infected sedentary and exercise mice lungs (n = 6 per group). *p < 0.05.

Figure 3.

Lung cytokines 48 hr after infection. Cytokines concentration per g of lung 48 hr after pneumonia induction in sedentary and exercise group. *p < 0.05 (n = 9 per group). IL = interleukin, TNF-α = tumor necrosis factor alpha.

Figure 4.

T-cell receptor evolution after infection. A, Absolute number of αβ T-cell receptor (TCRαβ) cells per lung at indicated time point after pneumonia induction (unpaired t test n = 6–12 per group). *p < 0.05. B, Absolute number of γδ T-cell receptor (TCRγδ) cells per lung at indicated time point after pneumonia induction (unpaired t test n = 6–12 per group). *p < 0.05.

Figure 5.

Alveolar macrophages (AMs) phenotype. A, CD64 expression on AMs, in the lungs of sedentary and exercise mice (n = 6 mice per group). *p < 0.05. B, Major histocompatibility complex (MHC) II expression on AMs, in the lungs of sedentary and exercise mice (n = 6 mice per group). *p < 0.05. C, Percentages of phagocytic AMs 2 hr after in vitro phagocytic assay of cells positive for green fluorescent protein (GFP) (GFPpos)-Escherichia coli with bronchoalveolar lavage of sedentary and exercised mice (n = 5–6 mice per groups). *p < 0.05. D, Percentages of phagocytic AMs after in vivo phagocytic assay of GFPpos-E. coli of sedentary and exercised mice (n = 5–6 mice per groups). *p < 0.05. gMFI = geometric mean fluorescence intensity.